The present application Novel Treatment for Posttraumatic Stress Disorder addresses the critical need for efficacious treatments for posttraumatic stress disorder (PTSD). A key neural signaling cascade activated by a trauma experience is initiated by the excitatory neurotransmitter glutamate. Activation of the NMDA receptor, a glutamate receptor subtype, results in subsequent activation of the enzyme neuronal nitric oxide synthase (nNOS) and, ultimately, an increase in the production of the signaling molecule nitric oxide (NO). These events trigger aberrant synaptic plasticity that is implicated in the initiation and maintenance of PTSD. Postsynaptic density protein 95 (PSD95) targets nNOS to the NMDA receptor and is, therefore, required for NMDA receptor activation of nNOS. Dr. Lai, Principal investigator for this project, first showed that the small molecule inhibitor IC87201 disrupts the functional protein-protein interaction between nNOS and PSD95 in vitro and attenuates NMDA receptor dependent hyperalgesia in vivo. Our preclinical team, led by Dr. Shekhar (Founder of Anagin), has now shown that IC87201 and a related analog, ZL006, block the long-term encoding of conditioned fear even after a fear conditioning session has occurred (i.e. post-trauma). Unlike NMDA receptor antagonists, these protein interaction inhibitors are efficacious without impairing motor movement or memory. Thus, disruption of signal compartmentalization represents an innovative approach to develop novel treatments for anxiety disorders with fewer side-effects. We have assembled a collaborative team with synergistic and complementary expertise to unite extensive combined experience in drug discovery (Lai), development of novel preclinical stress and memory models (Shekhar and Hohmann), chemical optimization of lead compounds (Thakur) and target validation (Lai and Hohmann) to conduct work proposed under two Specific Aims. Aim 1 of this proposal will characterize the pharmacokinetic profile and oral efficacy of our lead inhibitors. Aim 2 will then use a traditional drug medicinal chemistry approach to design and develop a back up chemical series with improved solubility and potency compared to the parent compounds. Results from this SBIR Phase I study will lay the foundation for further lead optimization and preclinical development of nNOS targeting inhibitors as novel treatments for PTSD in Phase II. These studies are expected to validate the disruption of signal protein compartmentalization as an innovative and feasible approach to drug development. The development of effective pharmacotherapies with novel chemical structures that possess limited side- effect profiles is expected to drive down escalating health care costs and alleviate unnecessary suffering in PTSD patients.